The biologic effects of marijuana and tobacco smoke on the lungs were evaluated in comparative companion studies. Tobacco smoke induced metabolic and structural alterations in alveolar macrophages, the key host defense cells of the lung, suggestive initially of phagocyte activation. The accompanying aberrant macrophage metabolism and intracellular accumulation of lipolysosomes, however, may be important to the pathogenesis of the analogues of bronchitis and emphysema demonstrable in the smoke-exposed animals. Specifically, derangements in oxygen metabolism within macrophages may produce potentially important mediators of lung inflammation and destruction. In addition, stereologic quantification of ultrastructural changes indicated an accumulation of enzyme-containing lipid-associated structures of potential pathogenic significance. With the exception of the responses of the airways, over comparable durations of exposure marijuana was dose for dose considerably less toxic than tobacco, even though the tobacco and marijuana smoke had essentially identical physical behavior under the conditions of study. The potential differences in the resultant biologic effects may be due to differences in animal-retained dosimetry, or to other as yet unidentified relationships.